Heterocyclic compounds

ABSTRACT

A group of heterocyclic compounds generally exhibiting central nervous system activity (such as depressant and anti-convulsant activities) and, in some cases, cardiovascular and/or anti-inflammatory activity are described. The compounds have the formula ##STR1## where A is an ethyl or propyl group which is mono-substituted by defined substituents or a di(loweralkyl)amino (loweralkoxy) carbonyl group and R is a phenyl group which may be substituted by defined substituents.

This application is a continuation-in-part of my earlier-filedapplication Ser. No. 373,046, filed June 25, 1973 and now abandoned.

The present invention provides a new substituted piperidines usefulpharmacologically and/or as intermediates for the preparation of similarcompounds. The invention also concerns processes for the preparation ofthe new compounds and pharmaceutical compositions containing them.

The invention presents new compounds of the formula I ##STR2## and theirpharmaceutically acceptable acid addition salts, wherein A represents amember selected from the class consisting of

I. ALKYL CONTAINING 2 TO 3 CARBON ATOMS MONO-SUBSTITUTED BY ASUBSTITUENT SELECTED FROM HYDROXYL, DI(LOWER ALKYL)-AMINO, CYANO,HALOGEN, GROUPS OF THE FORMULA --CO.NX.Y where X and Y are selected fromhydrogen and lower alkyl, groups of the formula --CO.T where T is loweralkyl, the semicarbazone and phenyl hydrazone derivatives of said groupsof the formula --CO.T, (lower alkoxy)carbonyl and groups of the formula--N(CH₂ R¹)R² where R¹ is selected from phenyl, monohalophenyl,mono(lower alkyl)phenyl and mono(lower alkoxy)phenyl and R² is pyridyl;and

II. DI(LOWER ALKYL)AMINO(LOWER ALKOXY) CARBONYL; AND

R represents a member selected from the class consisting of phenyl andphenyl substituted by one to two substituents selected from lower alkyl,halogen, and nitro.

The term "lower" as applied to a radical or group denotes that theradical or group contains up to 6 carbon atoms, preferably up to 4carbon atoms. As lower alkyl groups there may be mentioned, forinstance, methyl, ethyl, n-propyl, i-propyl, n-butyl and n-hexyl. Aslower alkoxy groups there may be mentioned, for example, methoxy,ethoxy, propoxy, butoxy and hexoxy.

A first preferred subgenus of the invention consists of the compoundswhere A is alkyl containing 2 to 3 carbon atoms mono-substituted bygroups of the formula --N(CH₂ R¹)R² where R¹ and R² are as defined aboveor by the phenyl hydrazone derivative of the groups having formula--CO.T where T is as defined above. The preferred substituent is thegroups of formula --N(CH₂ R¹)R². R¹ may represent, for example, phenyl,chlorophenyl, bromophenyl, tolyl, ethylphenyl, methoxyphenyl orethoxyphenyl. R¹ preferably represents mono(lower alkoxy)phenyl,preferably methoxyphenyl. R² represents pyridyl, preferably 2-pyridyl.

The group A may also represent alkyl containing 2 to 3 carbon atomsmono-substituted by hydroxyl, di(lower alkyl)amino, preferablydi(ethyl)amino, cyano, halogen, particularly fluorine, chlorine, bromineand iodine, groups of the formula --CO.NX.Y where X and Y are selectedfrom hydrogen and lower alkyl, for instance --CONH₂, and (loweralkoxy)carbonyl, preferably methoxycarbonyl.

The aforesaid alkyl containing 2 to 3 carbon atoms is ethyl or propyl,preferably ethyl.

The group A may also represent di(lower alkyl)amino(loweralkoxy)carbonyl, preferably (diethylamino)ethoxycarbonyl.

As illustrative examples of A there may be particularly mentioned thoseof the formulae

    ______________________________________                                        CH.sub.2CH.sub.2Cl                                                             ##STR3##                                                                     CH.sub.2CH.sub.2OH                                                            CH.sub.2CH.sub.2CN                                                             ##STR4##                                                                      ##STR5##                                                                      ##STR6##                                                                      ##STR7##                                                                     (CH.sub.2).sub.3CO . NH.sub.2                                                 (CH.sub.2).sub.3CON(iPr)H                                                      ##STR8##                                                                      ##STR9##                                                                      ##STR10##                                                                     ##STR11##                                                                    ______________________________________                                    

A second preferred subgenus of the invention resides in the compoundswhere R is phenyl. In this case A is preferably as defined in connectionwith the first preferred subgenus.

R may also represent phenyl substituted with one to two substituentsindependently selected from lower alkyl, for instance, methyl, ethyl,propyl or butyl, halogen, particularly fluorine, chlorine, bromine, oriodine, and nitro. Examples of R includes phenyl, tolyl, dichlorophenyland nitrophenyl.

Examples of pharmaceutically acceptable acid addition salts are thoseformed from inorganic and organic acids, in particular such salts as thesulphate, hydrochloride, hydrobromide, hydroiodide, nitrate, phosphate,sulphonates (such as the methane-sulphonate and p-toluene-sulphonate),acetate, maleate, fumarate, tartrate and formate.

Some of the compounds of formula (I) are useful as intermediates for thepreparation of other compounds by reactions that modify the group A orR. The compounds of general formula (I) exhibit pharmacologicalactivity, for instance, they generally exhibit central nervous systemactivity (such as depressant or anti-convulsant activities) and somecompounds also have action on the cardiovascular system (such ashypotensive activity) and/or anti-inflammatory activity when tested onwarm-blooded animals.

The compounds of the invention may possess the R.CO.NH substituent atany of the carbon atoms of the piperidine ring. Compounds where thesubstitutent is at the 4-position, i.e. of formula ##STR12## arepreferred.

The new compounds of the invention may be prepared by building up themolecule by processes known per se. Thus, for example, the acyl groupRCO-- can be introduced by standard acylation procedures. A substitutedalkyl group represented by A can be introduced by alkylation. A di(loweralkyl)amino(lower alkoxy)carbonyl group represented by A can beintroduced by initial introduction of CO.Cl group and subsequentreaction with di(lower alkyl)amino(lower)alkanol. The piperidine ringcan be obtained by reduction of a pyridine ring.

The present invention provides a process for preparation of compounds offormula I and their salts, in which

a. a compound of formula ##STR13## (where A is as defined above) or anactivated amino derivative thereof is coupled with an acid of formulaRCO₂ H (where R is as defined above) or a reactive derivative thereof,or

b. a compound of formula ##STR14## (where R is as defined above) isreacted with di(lower alkyl)amino(lower)alkanol; or

c. a compound of formula ##STR15## or an acid addition salt thereof isreacted with an alkylating agent of formula A--Z where Z is a leavinggroup or atom and A is as defined above in connection with formula I orwith an agent that introduces a substituted alkyl group A by an additionreaction; or

d. a compound containing the ion ##STR16## where R and A are as definedabove is reduced, or

e. a compound of formula ##STR17## where R is as defined above and A' isalkyl of 2 to 3 carbon atoms monosubstituted by carboxyl or a derivativethereof or its acid addition salt is amidated to produce the compoundwhere A is alkyl of 2 to 3 carbon atoms monosubstituted by thesubstituted or unsubstituted carbamoyl group ##STR18## where X and Y areselected from hydrogen and lower alkyl. The process may further includea step in which a compound of formula I or an acid addition salt thereofis converted to a further compound and if desired a compound of formulaI is converted into an acid addition salt thereof or an acid additionsalt is converted into a compound of formula I.

Compounds of the invention may be prepared by introduction of the RCO--acyl groups by standard coupling methods [see, for example, "TheChemistry of The Amino Acids" by Greenstein and Winitz (John Wiley &Sons, Inc.)]. Acyl groups can be introduced by direct reaction of acarboxylic acid with the amino group in the presence of afunctionalising or dehydrating agent. The acid may instead be reactedwith an activated amino derivatives of the compound of formula II. Acylgroups may also be introduced by reaction of the compound of formula IIwith an acylating derivative of the acid RCOOH. As acylating derivativesthere may be mentioned the carboxylic acid halides, preferably the acylchloride, the simple or mixed anhydrides of the acid, active esters andazides.

Where it is desired to obtain final products containing a functionalgroup susceptible to acylation the starting material used may contain achemically protected form of the group or an appropriate precursor fromwhich the function may be subsequently generated. Thus, for example, afree hydroxy group may be generated by removing a chemical blockinggroup or by reduction of a carbonyl group. Phenylhydrazones andsemicarbazones may be obtained by reaction of the corresponding ketonewith phenylhydrazine or semicarbazide.

The compounds of the invention may also be prepared by reacting acompound of formula ##STR19## with an alkylating agent of formula A--Zwhere Z is a leaving group or atom and A is substituted ethyl or propyl.As examples of such alkylating agents there may be mentioned substitutedethyl or propyl halides for example, the chlorides or bromides.

Certain classes of substituted alkyl groups A may be introduced byaddition reactions. Thus, for example, compounds where A represents aα-hydroxy alkyl group may be made by reacting an epoxide such asethylene oxide or propylene oxide with the compound of formula (IV).Moreover, β-oxoalkyl groups may be introduced by reacting the compoundof formula IV with an α, β-unsaturated ketone. The following areexamples of such reactions: ##STR20## where T is a lower alkyl group.

Compounds of the invention may also be prepared by reacting a compoundof formula (IV) with phosgene to form compounds of the formula ##STR21##and subsequent reaction with a di(lower alkyl)amino(lower)alkanol.

The piperidine ring in the compounds of the invention may be introducedby reduction of a corresponding compound with a pyridine ring. Thereduction may be effected by catalytic hydrogenation or a hydridetransfer agent for example, an alkali metal borohydride. In such methodsa reducible function in A may be reduced, for example, compounds where Ais an oxo-alkyl group may be reduced to a hydroxy-substituted alkylgroup A.

Once a compound of general formula (I) has been prepared, then ifnecessary or desired one or more substituents in the molecule may beconverted to another substituent each within its own meanings specifiedin connection with formula (I).

For example if a compound of formula (I) is prepared in which the chainA contains a carbonyl function, then this chain may be reduced. Forexample, a keto-alkyl group may be reduced to form a free hydroxy groupwith an alkali metal borohydride. A hydroxy alkyl group A may beconverted into a haloalkyl group in known manner. A cyanoalkyl group Amay be hydrolysed to form alkyl substituted by carbamoyl. A haloalkylgroup A may be converted into a substituted or unsubstituted aminoalkylgroup A in known manner.

The invention also provides a process for the preparation of the newcompounds of formula I and their acid addition salts where A representsthe alkyl group monosubstituted by a carbamoyl group of formula##STR22## where X and Y are selected from hydrogen and lower alkyl,wherein a corresponding compound where A represents the alkyl groupmono-substituted by carboxyl or a derivative thereof, for instance,lower alkoxycarbonyl, is amidated.

In order to prepare a compound of general formula (I) in which Arepresents a phenylhydrazone or semicarbazone of an oxo-alkyl radical,the corresponding ketone is converted into the desired derivative bymethods known in the literature. In this respect reference may be madeto (I) Reagents for Organic Synthesis by L. Fieser and M. Fieser (JohnWiley & Sons, Inc., 1967) at page 434 and 479; (2) U.K. PatentSpecification 1,223,491; and (3) A Scheme of Qualitative OrganicAnalysis by F. J. Smith and E. Jones (Blackie & Son Ltd., 1960) at page38.

The starting materials for the above mentioned processes for thepreparation of the new compounds of the invention are accessible byknown methods or, in certain cases, known per se.

The invention further includes pharmaceutical compositions containing asactive ingredients a compound of formula (I) or a pharmaceuticallyacceptable acid addition salt thereof which may be micronized ifdesired. In addition to the active ingredient, said compositions alsocontain a non-toxic carrier. Any suitable carrier known in the art canbe used to prepare the pharmaceutical compositions. In such acomposition, the carrier may be a solid, liquid or mixture of a solidand a liquid. Solid form compositions include powders, tablets andcapsules. A solid carrier can be one or more substances which may alsoact as flavouring agents, lubricants, solubilisers, suspending agents,binders, or tablet-disintegrating agents; it can also be anencapsulating material. In powders the carrier is a finely divided solidwhich is in admixture with the finely divided active ingredient. Intablets the active ingredient is mixed with a carrier having thenecessary binding properties in suitable proportions and compacted inthe shape and size desired. The powders and tablets preferably containfrom 5 to 99, preferably 10-80% of the active ingredient. Suitable solidcarriers are magnesium carbonate, magnesium stearate, talc, sugar,lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose,sodium carboxymethyl cellulose, a low melting wax, and cocoa butter. Theterm "composition" is intended to include the formulation of an activeingredient with encapsulating material as carrier to give a capsule inwhich the active ingredient (with or without other carriers) issurrounded by carrier, which is thus in association with it. Similarlycachets are included.

Sterile liquid form compositions include sterile solutions, suspensions,emulsions, syrups and elixirs. The active ingredient can be dissolved orsuspended in a pharmaceutically acceptable sterile liquid carrier, suchas sterile water, sterile organic solvent or a mixture of both.Preferably a liquid carrier is one suitable for parenteral injection.Where the active ingredient is sufficiently soluble it can be dissolvedin normal saline as a carrier; if it is too insoluble for this it canoften be dissolved in a suitable organic solvent, for instance aqueouspropylene glycol or polyethylene glycol solutions. Aqueous propyleneglycol containing from 10 to 75% of the glycol by weight is generallysuitable.

In other instances compositions can be made by dispersing thefinely-divided active ingredient in aqueous starch or sodiumcarboxymethyl cellulose solution, or in a suitable oil, for instancearachis oil. Liquid pharmaceutical compositions which are sterilesolutions or suspensions can be utilised by intramuscular,intraperitoneal or subcutaneous injection. In many instances a compoundis orally active and can be administered orally either in liquid orsolid composition form.

Preferably the pharmaceutical composition is in unit dosage form. Insuch form, the composition is sub-divided in unit doses containingappropriate quantities of the active ingredient; the unit dosage formcan be a packaged composition, the package containing specificquantities of compositions, for example packeted powders or vials orampoules. The unit dosage form can be a capsule, cachet or tabletitself, or it can be the appropriate number of any of these in packageform. The quantity of active ingredient in a unit dose of compositionmay be varied or adjusted from 5 mg. or less to 500 or more, accordingto the particular need and the activity of the active ingredient. Theinvention also includes the compounds in the absence of carrier wherethe compounds are in unit dosage form.

The following non-limiting Examples illustrate the invention:

EXAMPLE 1 1-(2-Chloroethyl)-4-benzamidopiperidine

a. A mixture of 2.04 grams (0.01 mole) of 4-benzamidopiperidine, 1.25grams (1 equivalent) of 2-bromoethanol and 2.76 grams (4-equivalents) ofpotassium carbonate were stirred at 100° C in 2 milliliters of methylethyl ketone for two hours. The mixture was filtered hot and theinorganic residue was washed well with hot methyl ethyl ketone. Thefiltrate was evaporated to dryness and the resulting white solidrecrystallised from ethyl acetate to give 1.55 grams (62%) of1-(2-hydroxyethyl)-4-benzamidopiperidine.

b. 1 Gram of 1-(2-hydroxyethyl)-4-benzamidopiperidine suspended in 2milliliters of dry benzene was treated with 0.62 gram of thionylchloride. The stirred mixture was refluxed for 3 hrs., then cooled andfiltered to give the title compound as a light grey solid.Crystallisation from ethanol-ether of this hydrochloride gave 0.8 grams(62%) of pale yellow needles, melting point 238.5° C.

Analysis: C₁₄ H₁₉ ClN₂ O.HCl requires C, 55.45%; H, 6.65% N, 9.24%.Found: C, 55.42%; H, 6.85%; N, 9.29%

EXAMPLE 2 4-Benzamido-1-(3-oxobutyl)piperidine

8.16 Grams of 4-benzamidopiperidine were dissolved in 60 milliliters ofethanol containing 4.68 grams of methyl vinyl ketone. The solution wasstirred at room temperature for 3 hours then left overnight. On makingthe solution acid with ethanolic HCl 9.92 grams (80% yield) of theproduct as its hydrochloride crystallised out. Recrystallisation fromethanol gave the pure title compound hydrochloride as colourlessneedles, m.p. 308°-310° C.

(Analysis: Found, C, 61.54%, N, 7.53%; N, 9.13%. C₁₆ H₂₂ N₂ O₂.HClrequires C, 61.82%; H, 7.46%; N, 9.01%).

EXAMPLE 3 4-Benzamido-1-(3-semicarbazonbutyl)piperidine

6.22 Grams of the product of Example 2, semicarbazide hydrochloride(2.24 g.) and ammonium acetate (4.8 g.) were dissolved in water (40 ml.)and kept at room temperature for 1 hour. The product which crystallisedout was collected and dried to give the title compound hydrochloride,quarter hydrate (5.05 g), melting point 155°-6°.

Analysis: Found, C, 54.96%; H, 7.27%; N, 18.99%. C₁₇ H₂₅ N₅ O₂.HCl.1/4H₂ O requires C, 54.82%; H, 7.25%; N, 18.81%).

EXAMPLE 4 4-Benzamido-1-(3-phenylhydrazonobutyl)piperidine

The title compound was obtained as a hydrochloride, sesquihydrate,melting point 168°-170° C, by following the procedure of the foregoingexample but using phenylhydrazine hydrochloride in place ofsemicarbazide hydrochloride.

(Analysis: Found, C, 62.09%; H, 7.42%; H, 13.23%. C₂₂ H₂₈ N₄O.HCl.11/2H₂ O requires C, 61.75%; H, 7.53%; N, 13.10%).

EXAMPLE 5 4-Benzamido-1-(2-diethylaminoethyl)piperidine

Equimolar amounts of 2-diethylaminoethyl chloride, hydrochloride and4-benzamidopiperidine were stirred under reflux in isopropanol with 2.5molar equivalents of anhydrous potassium carbonate for 18 hours. The hotsuspension was filtered and the filtrate was treated with ethereal HClto give the title compound as a dihydrochloride, hemihydrate, m.p.<220°(with decomp.)

(Analysis: Found: C, 56.67%; H, 8.42%; N, 10.82%; C₁₈ H₂₉ N₃O.2HCl.1/2H₂ O requires C, 56.09%; H, 8.37%; N, 10.90%).

EXAMPLE 6 β-Diethylamino)ethyl-4-benzamidopiperidine-1-carboxylate

a. 4-Benzamidopiperidine-1-carbonyl chloride

Phosgene was bubbled into dry toluene (75 ml) until 3.71 g. (0.0375mole) had dissolved. To this solution was added a suspension of4-benzamidopiperidine (5 g., 0.025 mole) in dry toluene (120 ml). Themixture was heated under reflux for one hour and the solvent wasevaporated to give a residue of the title compound (5g., 75%).

b. Sodium (0.432 g., 0.0188 mole) was added to β-diethylaminoethanol(2.23 g., 0.0190 mole) in dry toluene (80 ml) and the mixture wasrefluxed to give a complete solution. 4-Benzamidopiperidine-1-carbonylchloride (4.2 g., 0.01575 mole) in suspension in dry toluene (150 ml.)was added in portions and the mixture refluxed for 21/2 hours. Water wasadded to the mixture, the toluene layer was collected, dried andevaporated to give the title compound (3.27 g. 37%), melting point78°-82° C.

Analysis: C₁₉ H₂₉ N₃ O₃ requires C, 65.67%; H, 8.41%; N, 12.09%. Found:C, 65.38%; H, 8.26%; N, 11.87%.

EXAMPLE 7

a. 4-Benzamido-1-(3-methoxycarbonylpropyl)piperidine

An intimate mixture of 4-benzamidopiperidine (2.0g.), methyl4-bromobutyrate (2.0g.) and potassium carbonate (1.5 g.) was stirred andheated on a steam bath for 15 minutes. An exothermic reaction occuredand the semi-molten mixture set solid. Trituration with water (20 ml.)and filtration provided the title compound (2.41 g., 82%), m.p. 116°

Found: C, 67.10; H, 8.00; N, 9.39; C₁₇ H₂₄ N₂ O₃ requires C, 67.08; H,7.95; N, 9.20%).

b. 4-Benzamido-1-(3-carbamoylpropyl)piperidine4-Benzamido-1-(3-methoxycarbonylpropyl)piperidine (5.0g.) in 0.880ammonia solution (50 ml.) was heated in a sealed tube at 105° for 18hours. The tube was cooled and opened and the resulting crystals werecollected and dried to give the title compound (2.53 g.) m.p. 199° C.

(Analysis: Found: 66.56%; H, 8.04%; N, 14.30%. C₁₆ H₂₃ N₃ O₂ requires C,66.41%, H, 8.01%; N, 14.52%).

EXAMPLE 8 4-(4-Benzamidopiperidino)butyric acid isopropyl amide

A mixture of 4-benzamidopiperidine(2.0g.),4-chloro-N-isopropylbutyramide (1.8g.) and potassium carbonate(1.5g.) was finely ground and heated with stirring on a steam bath for10 minutes. Trituration with water and filtration gave a solid (1.64 g.)which was dissolved in ethanolic HCl and diluted with ethyl acetate togive the crude product hydrochloride. Recrystallisation fromacetonitrile/ether/ethyl acetate/methanol provided the title compoundhydrochloride, quarterhydrate, m.p. 217° C.

(Found: C, 61.18; H, 7.94; N, 10.96. C₁₉ H₂₉ N₃ O₂.HCl.1/4H₂ O requiresC, 61.27; H, 8.25; N, 11.28%).

EXAMPLE 9

4-Benzamido-1-(3-cyanopropyl)piperidine

Prepared in the same way as Example 7 (a) but using4-chlorobutyronitrile as the alkylating agent, the title compound meltedat 237° C (Found: C, 62.66%; H, 7.25%, N, 13.52%. C₁₆ H₂₁ N₃ O requiresC, 62.42%; H, 7.21%; N, 13.65%).

EXAMPLE 10 1-(2-hydroxyethyl)-4-benzamidopiperidine

20.43 Grams (0.1 mole) of 4-benzamidopiperidine, 15.0 grams (20% excess)of 2-bromoethanol, 27.6 grams (0.2 mole) of potassium carbonate and 20millilitres of methyl ethyl ketone were heated and stirred at 100° C for2 hours. The mixture was filtered hot to remove inorganic material andthe filtrate was evaporated to give 14.34 grams of a white solid whichwas recrystallised from ethyl acetate to give 13.56 grams of the titlecompound. Yield: 54.6%. Melting point: 133.3° C. The hydrochloride(melting point 189.1° C) was obtained by dissolving the base inethanolic hydrogen chloride and adding ether to induce crystallisation.

Analysis: C₁₄ H₂₀ N₂ O₂.HCl requires C, 59.05%; H, 7.43%; N, 9.84%.Found: C, 59.28%; H, 7.58%; N, 9.67%.

EXAMPLE 114-Benzamido-1-(2-[N-(p-methoxybenzyl)-N-(2-pyridyl)]-amino)ethylpiperidine

To 50 ml. of liquid ammonia was added 89 milligrams of lithium wire inportions followed after first addition by a few crystals of ferricnitrate. When the initial blue colour had disappeared and the lithiumhad all dissolved the ammonia was allowed to evaporate. To the solidlithium amide was added 2-[p-methoxybenzyl]aminopyridine (928 mg.,0.0043 mole) in 50 ml. dry benzene. The mixture was refluxed for 2 hoursbefore adding over 20 minutes solid1-(2-chloroethyl)-4-benzamidopiperidine (1.33 g., 0.005 mole). Refluxingwas continued for 61/2 hours before cooling and filtering. To thefiltrate was added petroleum ether (b.p. 60°-80°) and on standing at 0°for 24 hours a yellow solid (585 mg.) was precipitated and filtered off.The mother liquor was evaporated to give a residue which gave 830 mg. ofalmost pure title compound (m.p. 129.7° C) after washing in ether. Arecrystallisation from aqueous methanol gave the title compound as itshemihydrate, m.p. 134.2° C.

[C₂₇ H₃₂ N₄ O₂.1/2H₂ O requires C, 71.48; H, 7.33; N, 12.35%. Found: C,71.85; H, 7.23; N, 12.34%].

EXAMPLE 12

a. 1-(3-Chloropropyl)-4-(2-methylbenzamido)piperidine

The title compound is prepared in a similar manner to Example 1(a) and(b) using 4-(2-methylbenzamido)piperidine and 3-bromopropanol asstarting materials in part (a).

b. 1-[3-(N-benzyl-N-2-pyridylamino)propyl]-4-(2-methylbenzamido)piperidine

The title compound is prepared in a similar manner to Example 11 from1-(3-chloropropyl)-4-(2-methylbenzamido)piperidine and2-(benzylamino)pyridine.

EXAMPLE 13

a. 1-(2-Chloroethyl)-4-(2,6-dichlorobenzamido)piperidine The titlecompound is prepared in a manner similar to Example 1(a) and (b) using4-(2,6-dichlorobenzamido) piperidine instead of 4-benzamidopiperidine.

b.4-(2,6-Dichlorobenzamido)-1-(2-[N-(p-methylbenzyl)-N-(2-pyridyl)amino]ethyl)piperidine

The title compound is prepared in a manner similar to Example 11 using1-(2-chloroethyl)-4-(2,6-dichlorobenzamido)piperidine and2-(p-methylbenzyl)aminopyridine.

EXAMPLE 14

a. 1-(2-Chloroethyl)-4-(p-nitrobenzamido)piperidine

The title compound is prepared in a similar manner to Example 1(a) and(b) using 4-(p-nitrobenzamido)piperidine instead of4-benzamidopiperidine.

b. 1-(2-[N-(p-Chlorobenzyl)-N-(2-pyridyl)amino]ethyl)-4-(p-nitrobenzamido)piperidine

The title compound is prepared in a manner similar to Example 11 using1-(2-chloroethyl)-4-(p-nitrobenzamido)piperidine and2-(p-chlorobenzyl)aminopyridine.

What is claimed is:
 1. A compound selected from those of the formula##STR23## and their pharmaceutically acceptable acid addition salts,wherein A represents a member selected from the class consisting ofi.alkyl containing 2 to 3 carbon atoms monosubstituted by a substituentselected from hydroxyl, di(lower alkyl)amino, cyano, halogen, groups ofthe formula --CO.NX.Y where X and Y are selected from hydrogen and loweralkyl, the semicarbazone derivatives of groups of the formula --CO.Twhere T is lower alkyl and groups of the formula--N(CH₂ R¹)R² where R¹is selected from phenyl, monohalophenyl, mono(lower alkyl)phenyl andmono(lower alkoxy) phenyl and R² is pyridyl; and ii. di(loweralkyl)amino(lower alkoxy)carbonyl; and R represents a member selectedfrom the class consisting of phenyl and phenyl substituted by one or twosubstituents selected from lower alkyl, halogen and nitro.
 2. A compoundas defined in claim 1, where A represents alkyl containing 2 to 3 carbonatoms monosubstituted by a substituent selected from groups of theformula --N(CH₂ R¹)R² where R¹ and R² are as defined in claim
 1. 3. Acompound as defined in claim 1 where R is phenyl.
 4. A compound asdefined in claim 1, which is 1-(2-chloroethyl)-4-benzamidopiperidine. 5.A compound as defined in claim 1, which is1-(2-hydroxyethyl)-4-benzamidopiperidine.
 6. A compound as defined inclaim 1, which is 4-benzamido-1-(3-semicarbazonobutyl)piperidine.
 7. Acompound as defined in claim 1, which is4-benzamido-1-(2-diethylaminoethyl)piperidine.
 8. A compound as definedin claim 1, which isβ-(diethylamino)ethyl-4-benzamidopiperidine-1-carboxylate.
 9. A compoundas defined in claim 1, which is4-benzamido-1-(3-carbamoylpropyl)piperidine.
 10. A compound as definedin claim 1, which is 4-(4-benzamidopiperidino) butyric acid isopropylamide.
 11. A compound as defined in claim 1, which is4-benzamido-1-(3-cyanopropyl)piperidine.
 12. A compound as defined inclaim 1, which is4-benzamido-1-(2-[N-(p-methoxybenzyl)-N-(2-pyridyl)]amino)ethylpiperidine.